This invention relates generally to the field of compound delivery for obtaining both local and systemic results. More particularly, it relates to a non-invasive method of compound delivery through the epidermis by means of increasing the permeability of skin through the use of chemical enhancers and sonophoresis and the synergetic simultaneous use of iontophoresis, electroporation, mechanical vibrations and magnetophoresis for optimizing transcutaneous compound delivery into the body.
The human skin has barrier properties and stratum corneum is mostly responsible for them, thus it is exactly the statum corneum, the outer horny layer of the skin, that imposes the greatest barrier to transcutaneous flux of compounds into the body.
The low permeability attributed to the stratum corneum, a complex structure comprised of multi-layered compact keratinized cells; low permeability is due to dead cells filled with keratin fibers (keratinocytes) surrounded by highly-ordered structure of lipid bilayers (Flynn, G. L., In Percutaneous Absorption: Mechanisms-Methodology-Drug Delivery.; Bronaugh, R. L., Maibach, H. I. (Ed), pages 27-53, Marcel Dekker, New York, 1989).
The stratum corneum hasn""t constant thickness, since it depends on each particular area, being thinner in areas subject to folds and much thicker in the hands palms and feet soles, is a very resistant waterproof membrane that both protects the body from invasion by exterior substances and the outward migration of fluids and dissolved molecules and creates a mechanical and biological shield between the environment and the interior of the body. The stratum corneum is continuously renewed by shedding of dead cells during desquamation and the formation of new corneum cells by the keratinization process.
Considering the permeation of compounds with non-charged molecules into the skin the flux of said compound across the epidermis is controlled by Fick""s First Law which states that this flux depends on the diffusion coefficient and on the gradient of concentration of the compound. One important issue to be remebered is that the diffusion coefficient is strongly dependent on the degree of hydration of the skin, significantly increasing with it.
Therefore one of the ways of enhancing the flux of compounds into the body is through the so-called penetration or chemical enhancers which increase the coefficient of diffusion of the stratum corneum and may be associated with sonophoresis, that is, ultrasound energy.
From the physical standpoint ultrasound waves have been defined as mechanical pressure waves with frequencies above 20 KHz, H. Lutz et al., Manual Of Ultrasound 3-12 (1984), are generated by either natural or synthetic materials that show the so-called piezoelectric property, meaning that these materials both generate an electric field when mechanically stressed (direct piezoelectric effect) and also generate a mechanical force when an electric field is conveniently applied to them (inverse piezoelectric effect).
These properties have been first established by Pierre and Jacques Curie who have observed their ocurrence in natural materials like the Rochelle salt; however in our days synthetic piezoceramic materials are preferred instead due to their more stable properties since they are not hygroscopic and also to the possibility of being manufactured in any shape, allowing a lot of different applications.
Ultrasound has also been used to enhance permeability of the skin and synthetic membranes to compounds and other molecules and its use to increase the permeability of the skin to compound molecules has been called sonophoresis or phonophoresis meaning transportation through sound like waves.
U.S. Pat. No. 4,309,989 to Fahim describes a method of topically applying an effective medication in an emulsion coupling agent by ultrasound. More particularly, a method of treating a skin condition by applying a medication in an emulsion coupling agent and massaging it into the affected area with ultrasonic vibrations thereby causing the medication to penetrate into the skin. Specifically, a method and composition for the treatment of Herpes Simplex Type 1 and Type 2 lesions. Also specifically, a method and composition for the treatment of demidox mites. U.S. Pat. No. 4,372,296 to Fahim similarly describes treatment of acnes by topical application of zinc sulfate and ascorbic acid in a coupling agent.
U.S. Pat. No. 4,767,402 to Kost et al. discloses a method using ultrasound to enhance permeation of molecules through the skin and into the blood stream, at a controlled rate. Depending on the compound being infused through the skin, the rate of permeation is increased as well as the efficiency of transfer. Drugs which may not be effective under other conditions, for example, due to degradation within the gastrointestinal tract, can be effectively conveyed transdermally into the circulatory system by means of ultrasound. Ultrasound is used in the frequency range of between 20 KHz and 10 MHz, the intensity ranging between 0 and 3 W/cm.sup.2. The molecules are either incorporated in a coupling agent or, alternatively, applied through a transdermal patch.
U.S. Pat. No. 4,780,212 to Kost et al. teaches use time, intensity, and frequency control to regulate the permeability of molecules through polymer and biological membranes. Further, the choice of solvents and media containing the molecules also affects permeation of the molecules through the membranes.
U.S. Pat. No. 4,821,740 to Tachibana et al. discloses an endermic application kit for external medicines, which comprises a drug-containing layer as provided near an ultrasonic oscillator. The kit includes a cylindrical fixed-type or portable-type and a flat regular-type or adhesive-type, and the adhesive-type may be flexible and elastic. The drug absorption is ensured by the action of the ultrasonic waves from the oscillator and the drug release can be controlled by varying the ultrasonic wave output from the oscillator.
U.S. Pat. No. 5,007,438 to Tachibana et al. is described an application kit in which a layer of medication and an ultrasound transducer are disposed within an enclosure. The transducer may be battery powered. Ultrasound causes the medication to move from the device to the skin and then the ultrasound energy can be varied to control the rate of administration through the skin.
U.S. Pat. No. 5,115,805 to Bommannan et al. discloses a method for enhancing the permeability of the skin or other biological membrane to a material such as a drug is disclosed. In the method, the drug is delivered in conjunction with ultrasound having a frequency of above about 10 MHz. The method may also be used in conjunction with chemical permeation enhancers and/or with iontophoresis. It is informed but not shown that chemical penetration enhancers and/or iontophoresis could be used in connection with the ultrasound treatment.
U.S. Pat. No. 5,444,611 to Eppstein et al. describes a method of enhancing the permeability of the skin or mucosa to a biologically active permeant or drug utilizing ultrasound or ultrasound plus a chemical enhancer.
Ultrasound can be modulated and frequency modulated ultrasound from high to low frequency can develop a local pressure gradient directed into the body. The method is also useful as a means for application of a tatoo by nininvasively delivering a pigment through the skin surface. Due to the completeness of that disclosure, the information and terminology utilized therein are incorporated herein by reference.
U.S. Pat. No. 6,041,253 to Kost et al. describes a method for transdermal transport of molecules during sonophoresis (delivery or extraction) further enhanced by application of an electric field, for example electroporation of iontophoresis. This method provides higher drug transdermal fluxes, allows rapid control of transdermal fluxes, and allows drug delivery or analyte extraction at lower ultrasound intensities than when ultrasound is applied in the absence of an electric field. Due to the completeness of that disclosure, the information and terminology utilized therein are incorporated herein by reference.
U.S. Pat. No. 6,234,990 to Rowe et al. discloses methods and devices for application of ultrasound to a small area of skin for enhancing trasdermal transport. An ultrasound beam having a first focal diameter is channelled into a beam having a second,smaller diameter without substantial loss of energy. A two step noninvasive method involves application of ultrasound to increase skin permeability and removal of ultrasound followed by transdermal transport that can be further enhanced using a physical enhancer. Due to the completeness of that disclosure, the information and terminology utilized therein are incorporated herein by reference.
Many other references teach use of ultrasound to deliver drugs through the skin, including Do Levy et al., 83 J. Clin. Invest. 2074 (1989); P. Tyle and P. Agrawala, 6 Pharmaceutical Res. 355 (1989); F. L. Henley, 65th Annual Conference of the American Physical Therapy Association, Anhaheim, Calif. (1990); H. Benson et al., 8 Pharmaceutical Res. (1991); D. Bommannan et al., 9 Pharmaceutical Res. 559 (1992); K. Tachibana, 9 Pharmaceutical Res. 952 (1992); T. Wong, Proceedings of the Joint Congress of the American Physical Therapy Association, Toronto, Ontario, Canada (1994); N. N. Byl, Physical Therapy, Volume 75, Number 6, (1995).
Many authors report the success of application of sonophoresis, J. Griffin and J. Touchstone, 42 Am. J. Phys. Med. 77 (1963); J. Griffin et al., 44 Am. J. Phys. Med. 20 (1965); J. Griffin et al., 47 Phys. Ther. 594 (1967); J. Davick et al., 68 Phys. Ther. 1672 (1988); D. Bommannan et al., 9 Pharm. Res. 559 (1992), while others have obtained negative results, J. McElnay et al., 20 Br. J. Clin. Pharmacol. 4221 (1985); H. Pratzel et al., 13 J. Rheumatol. 1122 (1986); H. Benson et al., 69 Phys. Ther. 113 (1988).
However recent studies of sonophoresis show that application of ultrasound at therapeutic frequencies of about 1 MHz induces growth and oscillations of air pockets present in the keratinocytes of the stratum corneum disorganizing the stratum corneum lipid bilayers thereby enhancing transcutaneous transport.
This means that permeation using only chemical enhancers and sonophoresis seems to be a limited process, therefore other physical principles must be added to improve the process in order to create a method for actively and safely enhancing the flux rate of compounds into the skin to a greater extent than can be achieved without their use.
From now on we will be concerned with ionic permeation, the transportation of charged particles, then we have to consider the general diffusion equation instead where Fick""s First Law must be added of a second term, an electric potencial gradient term, meaning another driving force created by an electrical field applied between the area under treatment and a referencial electrode, the so-called process of iontophoresis.
Electroporation is believed to work in part by creating transient pores in the lipid bilayers of the stratum corneum (Burnett (1989)).
Iontophoresis involves the topical delivery of either an ionized form of compound or an unionized compound carried with the water flux associated with ion transport, the process being termed electro-osmosis.
An electrical field is created between the area under treatment and a referencial electrode usually fixed to the right wrist of the individual, normally consisting of a variable electric field with selected properties like amplitude frequency, waveshape, polarity and duty cycle.
The polarity of the electric field depends on the pH of the chemicals to be delivered into the skin, therefore it must be accordingly selected by the user.
Low and medium frequency periodic mechanical vibrations created for example by rotating unbalanced masses applied to the skin surface create mechanical pressure waves that establish a pumping action, forcing the compounds into the skin, enhancing the permeation process.
Optimum results are obtained using time varying vibrations, resulting in several types of complex waveshapes like xe2x80x9csawtoothxe2x80x9d, xe2x80x9ctrianglexe2x80x9d, xe2x80x9con-offxe2x80x9d and xe2x80x9cstaircasexe2x80x9d among others, with fundamental frequencies in the range of 1 Hz to 1 KHz, but with several useful low order harmonic terms having amplitudes, frequencies and phases according to their respective expansion using Fourier""s series.
Finally, one more physical principles can be used to achieve further enhancement of flux rate: constant or time varying magnetic fields which can induce mechanical forces to charged particles in such a way to force them into the skin, the so-called process of magnetophoresis.
It is worthwhile to remember that also some heat is internally generated by sonophoresis and additionally also iontophoresis contributes with Joule""s effect originated heat, all them giving some contribution to the increase of temperature of the skin, thus some prevision must be made to keep this temperature under control.
An object of the present invention is to provide a method for fast active transcutaneous permeation of compounds through the human skin targeting obtaining either local or systemic results allowing,among others, the non-invasive painless treatment of cellulitis, localized fat, stretch marks and flacid skin.
Another object of the invention is to provide a method for the active transcutaneous permeation of compounds in a non invasive basis, allowing treatments with minimal occurrence of undesirable collateral effects.
A further object of the invention is to minimize the time of treatment through the synergetic simultaneous use of both chemical enhancers and several physical principles.
These and other objects may be accomplished by applying to the skin surface permeation enhancers and compounds simultaneously with physical permeability enhancers such as sonophoresis with modulated or non-modulated ultrasound, continuous or pulsed, iontophoresis, electroporation, mechanical vibrations and magnetophoresis.
Specially designed equipment and application device allowing the application of this method will be described herein.
Ultrasound energy also may also open up diffusional pathways in the stratum corneum, causing an increase in the permeability of that layer and causing frictional heat to be generated in deeper tissues, increasing the activity of both lymph and blood circulation, as well as of metabolic processes.
Due to the complete synergism and complementarity of these physical principles, their combined actions lead us to fast treatments when associated with ultrasound coupling products, chemical permeants, allowing compounds to be efficiently permeated through the skin, since both ultrasound, iontophoresis, electroporation, mechanical vibrations and magnetophoresis force chemical enhancers and compounds into the stratum corneum, thereby reducing the lag time associated with the non-enhanced (passive) diffusion process.